Monitoring Brain Neural Activity

ABSTRACT

Monitoring brain neural activity comprises repeatedly applying electrical stimuli to evoke neural responses in the brain. Neural responses evoked by the stimuli are recorded. The recorded neural responses are assessed for changed characteristics over time, to monitor a time-varying effect on the recorded neural responses of local field potentials arising from a source other than the electrical stimuli.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Australian Provisional Patent Application No. 2015902022 filed 31 May 2015, which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to neural modulation in the brain, and in particular relates to a method for monitoring neural responses in the brain evoked by electrical stimulation, and monitoring such recordings repeatedly over time, in order to detect and monitor local field potentials arising from other sources.

BACKGROUND OF THE INVENTION

Neuromodulation involves applying an electric stimulus to biological tissue in order to evoke compound action potentials (ECAPs) to produce a therapeutic effect. Neuromodulation can be non-invasive such as by transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), or highly invasive when requiring the implantation of one or more electrodes and a controlling stimulator as in the case of deep brain stimulation (DBS). DBS has become the most effective treatment for late stage Parkinson's disease, but is a highly invasive therapy requiring the implantations of one or more leads deep into subcortical nuclei and connection to one or more pulse generators implanted in the chest. Many DBS electrode target structures have been studied to treat a wide variety of diseases, and the preferred location of the electrode varies depending on the disease that is being treated. In the case of Parkinson's disease, the preferred targets are the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN). The GPi has also been targeted for Huntington's disease and Tourette's syndrome, the nucleus accumbens has been targeted for chronic depression and alcohol dependence, and the fornix, hypothalamus and nucleus basalis of Meynert have been targeted for Alzheimer's disease.

Parkinson's disease is a degenerative disorder affecting dopamine-releasing cells in the substantia nigra. Many theories describing the functioning of the basal ganglia and how this degeneration relates to Parkinson's disease have been proposed, however all such theories have significant inadequacies in describing all aspects of Parkinson's disease, and understanding the mechanisms of DBS remains the focus of considerable research effort.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

In this specification, a statement that an element may be “at least one of” a list of options is to be understood that the element may be any one of the listed options, or may be any combination of two or more of the listed options.

SUMMARY OF THE INVENTION

According to a first aspect the present invention provides a method of monitoring brain neural activity, the method comprising:

repeatedly applying electrical stimuli to evoke neural responses in the brain;

recording neural responses evoked by the stimuli,

assessing the recorded neural responses for changed characteristics over time, to monitor a time-varying effect on the neural responses of local field potentials arising from a source other than the electrical stimuli.

According to a second aspect the present invention provides a brain neurostimulator device comprising:

at least one stimulus electrode configured to be positioned in the brain and to deliver electrical stimuli to the brain;

at least one sense electrode configured to be positioned in the brain and to sense neural responses evoked by the stimuli;

a pulse generator configured to apply electrical stimuli from the at least one stimulus electrode to the brain;

measurement circuitry configured to record brain neural responses sensed by the at least one sense electrode in response to the electrical stimuli; and

a processor for assessing the recorded neural responses for changed characteristics over time, to monitor a time-varying effect on the neural responses of local field potentials arising from a source other than the electrical stimuli.

The present invention further provides computer software, or a computer program product comprising computer program code means, or a non-transitory computer readable medium, or a computing device operating under the control of said software or product, configured to repeatedly apply electrical stimuli to evoke neural responses in the brain, and further configured to record neural responses evoked by the stimuli, and further configured to assess the recorded neural responses for changed characteristics over time, to monitor a time-varying effect on the neural responses of local field potentials arising from a source other than the electrical stimuli.

The neurostimulator may comprise a deep brain stimulator.

Assessing the recorded neural responses for changed characteristics may comprise assessing the amplitude of the observed neural responses. The observed neural responses may be assessed in the frequency domain. Amplitude variations arising in the 0.6 to 3 Hz range may enable a heartbeat of the subject to be assessed. Such embodiments recognise that the heartbeat affects the local field potential at the recording electrodes mechanically or rheologically, introducing a modulation or fluctuation onto the observed ECAP amplitude.

Fluctuations in the amplitude of the observed evoked ECAPs in the 7-35 Hz range, also referred to as beta-band oscillations, may be indicative of a Parkinson's patient's OFF state, or in the 50-1000 Hz range may be indicative of a Parkinson's patient's ON state. Spectral analysis may enable some embodiments to simultaneously assess each such signal of neural activity from sources other than the neurostimulator.

It is thus to be understood that the local field potentials arising from a source other than the electrical stimuli is intended to encompass local field potential variations arising mechanically, rheologically, neurologically or the like. In the case of beta band oscillations in particular it is to be noted that the stimuli applied by the neurostimulator may effect a therapy which alters such beta band oscillations, even though such mechanisms are poorly understood. There is thus a distinction to be noted between a locally evoked neural response or ECAP which arises directly from a stimulus, and the separate contribution of a beta band oscillation which modulates the amplitude or spectral content of a series of such ECAPs over time. The separate contribution of beta band oscillations is to be understood as constituting a source other than the electrical stimuli and thus within the scope of some embodiments of the present invention.

The neural measurement is preferably obtained in accordance with the teaching of International Patent Publication No. WO2012/155183 by the present applicant, the content of which is incorporated herein by reference.

By monitoring a time-varying effect of local field potentials arising from a source or sources other than the electrical stimuli, some embodiments of the present invention may deliver a diagnostic method. The presence, amplitude, morphology, and/or latency of the neural response effects arising from the other source(s) may be compared to healthy ranges and/or monitored for changes over time in order to diagnose a disease state. The method of the invention may be applied in some embodiments in order to determine a therapeutic effect of the stimulation, determine a therapeutic effect of medicine, and/or to monitor disease state. A therapeutic response may subsequently be ordered, requested and/or administered based on the diagnosis.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the invention will now be described with reference to the accompanying drawings, in which:

FIG. 1 illustrates an implanted deep brain stimulator;

FIG. 2 is a block diagram of the implanted neurostimulator;

FIG. 3 is a schematic illustrating interaction of the implanted stimulator with brain tissue;

FIG. 4 illustrates the dynamics of evoked response amplitude in one patient on two separate recording channels, in the time domain,

FIG. 5 illustrates the frequency domain analysis of the dynamics of the ECAP amplitude;

FIG. 6 illustrates the spectrum of observed ECAPs in the STN; and

FIG. 7a shows an ECG spectrum, and FIG. 7b shows the spectrum of ECAPs, illustrating the presence of heartbeat in the ECAPs spectrum.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 schematically illustrates an implanted deep brain stimulator 100. Stimulator 100 comprises an electronics module 110 implanted at a suitable location in the patient's chest, and two electrode assemblies 150, 152 implanted within the brain and connected to the module 110 by a suitable lead. Numerous aspects of operation of implanted neural device 100 are reconfigurable by an external control device (not shown). Moreover, implanted neural device 100 serves a data gathering role, with gathered data being communicated to an external device.

FIG. 2 is a block diagram of the implanted neurostimulator 100. Module 110 contains a battery 112 and a telemetry module 114. In embodiments of the present invention, any suitable type of transcutaneous communication 190, such as infrared (IR), electromagnetic, capacitive and inductive transfer, may be used by telemetry module 114 to transfer power and/or data between an external device and the electronics module 110.

Module controller 116 has an associated memory 118 storing patient settings 120, control programs 122 and the like. Controller 116 controls a pulse generator 124 to generate stimuli in the form of current pulses in accordance with the patient settings 120 and control programs 122. Electrode selection module 126 switches the generated pulses to the appropriate electrode(s) of electrode arrays 150 and 152, for delivery of the current pulse to the tissue surrounding the selected electrode(s). Measurement circuitry 128 is configured to capture measurements of neural responses sensed at sense electrode(s) of the electrode arrays as selected by electrode selection module 126.

FIG. 3 is a schematic illustrating interaction of the electrode array 150 of implanted stimulator 100 with nerve tissue 180, in this case the subthalamic nucleus however alternative embodiments may be positioned adjacent any suitable brain structure. Array 152 is not shown in FIG. 3 but operates in an equivalent manner in the contralateral cerebral hemisphere. Electrode selection module 126 selects a stimulation electrode 2 of electrode array 150 to deliver an electrical current pulse to surrounding neural tissue 180, and also selects a return electrode 4 of the array 150 for stimulus current recovery to maintain a zero net charge transfer.

Delivery of an appropriate stimulus to the neural tissue 180 evokes a neural response comprising a compound action potential which will propagate along associated neural pathways, for therapeutic purposes.

The device 100 is further configured to sense the existence and intensity of compound action potentials (CAPs) propagating within neural tissue 180, whether such CAPs are evoked by the stimulus from electrodes 2 and 4, or otherwise evoked such as by the contralateral electrodes of array 152. To this end, any electrodes of the array 150 may be selected by the electrode selection module 126 to serve as measurement electrode 6 and measurement reference electrode 8. Signals sensed by the measurement electrodes 6 and 8 are passed to measurement circuitry 128, which for example may operate in accordance with the teachings of International Patent Application Publication No. WO2012155183 by the present applicant, the content of which is incorporated herein by reference.

The present invention recognises that the recorded neural responses measured as a function of the stimulus can provide a great deal of information about the neurons that are being stimulated and their characteristics. This information can play a vital role not only in choosing parameters for stimulation but also in monitoring the course of the disease. The shape of the compound action potential is directly related to the electrophysiology and the ion channel conductivities during the time course of the evolution of the action potential. The shape is reflective of the underlying ion channel behaviour which is in turn reflective of the underlying disease state.

The present invention recognises that a plethora of causes can change the response of the tissue to stimulation, including adaptation, changes in electrode micro environment co-incident with the heartbeat, a worsening of the state of the disease, the course of medication intake, the current overall state of the patient (sleep, rest, movement, etc.). Further, it is possible to use ECAPs to analyse dynamics of such other sources of neural activity.

Parkinson's disease has often been associated to an increase in beta-band oscillations which can be influenced by deep brain stimulation. We have shown that measurements of evoked compound action potentials (ECAPs) can be used to analyse the frequency spectrum of the signals in the brain by observing the modulation of the ECAP amplitude.

The modulation observed directly reflects slow oscillations in the brain and a feedback system can be designed that stimulates and records the slow waves in real-time by means of the ECAP amplitude. The feedback can be adjusted to optimise the stimulation parameters in order to minimise or maximise certain frequency bands (for example the beta-band for Parkinson's disease).

The frequency analysis of the ECAP features can also be used to extract other physiological information from the patient like the heartbeat that can help provide a more complete picture of the patient's state during the course of the disease. FIGS. 4 and 5 give an example of the dynamic changes that can be observed with the embodiment of the present invention.

FIG. 4 illustrates the dynamics of the |N1-P2| amplitude in one patient on two separate recording channels in the time domain. FIG. 5 shows the frequency analysis of the dynamics of the |N1-P2| amplitude on one of the patients.

Heartbeat induced fluctuations in the ECAP amplitude may for example be controlled by feedback, in order that the evoked response amplitude remains constant, or remains upon a desired locus, throughout each cardiac cycle. Additionally or alternatively, medication induced fluctuations in neural excitability and thus the ECAP amplitude may be controlled by feedback, in order for the evoked response amplitude to remain constant, or remain upon a desired locus, throughout the course of each dose of a medication such as L-dopa for Parkinson's disease.

Thus, the ECAP amplitude is modulated by slow potentials, making ECAP amplitude measurements a proxy measure for at least some of the observed frequency components. In the STN, the focus is guided toward beta-band oscillations, in the VIM, the tremor frequencies are considered.

FIG. 6 is a plot of the frequency components of the first 1000 consecutive stimuli (total measurement time of 7.7 seconds) for 4 different stimulation current amplitudes, in the right STN of Patient 1, as measured on electrode R4 with bipolar biphasic stimulation on electrodes R1/R2. Sharp low frequency peaks in the beta range of the type seen in FIG. 6 were observed in nearly every one of the five STN patients assessed, but the location of each peak varied from patient to patient and no net increase or decrease could be observed with increasing stimulus amplitude. For example, in Patient 1 in FIG. 6, a peak at 1.156 Hz was observed. The next peak appeared at roughly 7 Hz and was followed by periodic peaks at 7 Hz intervals with another peak at around 18 Hz. The peaks change across nuclei. The periodicity of the peaks suggests that most of the higher frequency peaks are harmonics of the same fundamental. This would suggest that in this patient, oscillatory behaviour at around 1 Hz, 7 Hz and 18 Hz is present in the signal.

The local field potentials (LFPs) sensed by the recording electrodes are the sum of all electrical activity in the tissue surrounding the electrodes. This activity thus has a modulatory effect on the observed ECAP amplitude. Phase amplitude coupling and pulsed inhibition are two known aspects of modulation of nerve excitability with LFPs. The lowest peak in the frequency spectrum was linked to heartbeat by simultaneous ECG and ECAP measurements in Patient 3, as shown in FIGS. 7a and 7b . In particular, the ECG spectrum of FIG. 7a shows a heartbeat contribution at 1.557 Hz (approx. 93 beats per minute), corresponding closely to and thus confirming the source of the peak at 1.56 Hz seen in the ECAP spectrum of FIG. 7b . In more detail, FIG. 7b shows the frequency spectrum of the ECAP amplitude on electrode R4 (right) at 2.5 mA stimulation with a pulse width of 90 μs and a frequency of 130 Hz in Patient 3. It is noted that Patient 3 was assessed in a Sao Paulo trial which suffered large measurement artefact leading to the apparent exponential spectral profile, but the peak at 1.56 Hz nevertheless emerges above the significant artefact in FIG. 7b , supporting the observation of heartbeat from the ECAP spectrum.

The origins of the other peaks at 7 Hz and 18 Hz in FIG. 6 are presently unknown, but even so they nevertheless present biomarkers which can be tracked over time and by which disease progression or other biological changes may be assessed. Oscillations in the beta range (8-35 Hz), as measured through LFPs, have been proposed as a biomarker for Parkinson's disease, and disruption of such oscillations has been proposed as a marker of the therapeutic effectiveness of DBS. Beta-band oscillations seem to play a role in PD and symptomatic relief through DBS therapy, but they cannot explain why levodopa (the most widely used anti-parkinsonian medication) and DBS, although having similar clinical effects, do not affect the beta-band oscillations in a similar way. Embodiments of the present invention provide a means whereby the effect of a given therapy on such oscillations may be effectively observed.

Thus it has been shown that the ECAP amplitude is modulated by at least some of the slow oscillations, including heartbeat, and can be used as a proxy to measure these frequency components. Some embodiments of the invention may therefore implement frequency analysis capability in the implant, where storage and processing is limited. By storing the ECAP amplitude at each shot, slow oscillations of frequencies of up to half the stimulus frequency (the Nyquist frequency) can be retrieved so long as they modulate the local field potential and thus the observed ECAP.

Some embodiments of the invention may thus provide a means whereby an implantable neurostimulator may detect neural activity arising from secondary sources, without the need to provide any additional sensors such as EEG, EMG or ECoG sensors or the like, and without even the need to interrupt therapeutic electrical stimulation. Such observations may in turn be used to determine a therapeutic effect of the stimulation, determine a therapeutic effect of medicine, and/or to monitor a disease state. A therapeutic response may subsequently be indicated, ordered, requested and/or administered based on the diagnosis.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not limiting or restrictive. 

1. A method of monitoring brain neural activity, the method comprising: repeatedly applying electrical stimuli to evoke neural responses in the brain; recording neural responses evoked by the stimuli, assessing the recorded neural responses for changed characteristics over time, to monitor a time-varying effect on the neural responses of local field potentials arising from a source other than the electrical stimuli.
 2. The method of claim 1, wherein assessing the recorded neural responses comprises assessing the amplitude of the observed neural responses.
 3. The method of claim 1 wherein assessing the recorded neural responses comprises assessing spectral content of the observed neural responses.
 4. The method of claim 3, further comprising assessing amplitude variations arising in a range of 0.6 to 3 Hz so as to assess a heartbeat.
 5. The method of claim 3, further comprising assessing amplitude variations arising in a beta-band oscillation range of 7-35 Hz.
 6. The method of claim 1 wherein the time-varying effect is compared to healthy ranges and/or monitored for changes over time in order to diagnose a disease state.
 7. The method of claim 1 wherein the to time-varying effect is compared to healthy ranges and/or monitored for changes over time in order to determine a therapeutic effect of a therapy.
 8. The method of claim 1, further comprising indicating a therapeutic response, based on the time-varying effect.
 9. A brain neurostimulator device comprising: at least one stimulus electrode configured to be positioned in the brain and to deliver electrical stimuli to the brain; at least one sense electrode configured to be positioned in the brain and to sense neural responses evoked by the stimuli; a pulse generator configured to apply electrical stimuli from the at least one stimulus electrode to the brain; measurement circuitry configured to record brain neural responses sensed by the at least one sense electrode in response to the electrical stimuli; and a processor for assessing the recorded neural responses for changed characteristics over time, to monitor a time-varying effect on the neural responses of local field potentials arising from a source other than the electrical stimuli.
 10. A computer program product comprising computer program code means for monitoring brain neural activity, the computer program code means configured to: repeatedly apply electrical stimuli to evoke neural responses in the brain; record neural responses evoked by the stimuli; and assess the recorded neural responses for changed characteristics over time, to monitor a time-varying effect on the neural responses of local field potentials arising from a source other than the electrical stimuli.
 11. The brain neurostimulator device of claim 9, wherein the processor is further configured to assess the recorded neural responses by assessing the amplitude of the observed neural responses.
 12. The brain neurostimulator device of claim 9 wherein the processor is further configured to assess the recorded neural responses by assessing spectral content of the observed neural responses.
 13. The brain neurostimulator device of claim 12 wherein the processor is further configured to assess amplitude variations arising in a range of 0.6 to 3 Hz so as to assess a heartbeat.
 14. The brain neurostimulator device of claim 12, wherein the processor is further configured to assess amplitude variations arising in a beta-band oscillation range of 7-35 Hz.
 15. The brain neurostimulator device of claim 9 wherein the processor is further configured to compare the time-varying effect to healthy ranges, and/or monitor the time-varying effect for changes over time, in order to diagnose a disease state.
 16. The brain neurostimulator device of claim 9 wherein the processor is further configured to compare the time-varying effect to healthy ranges, and/or monitor the time-varying effect for changes over time, in order to determine a therapeutic effect of a therapy.
 17. The brain neurostimulator device of claim 9 wherein the processor is further configured to indicate a therapeutic response, based on the time-varying effect. 